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- Title
First-in-Human Evaluation of the Safety and Immunogenicity of an Intranasally Administered Replication-Competent Sendai Virus-Vectored HIV Type 1 Gag Vaccine: Induction of Potent T-Cell or Antibody Responses in Prime-Boost Regimens.
- Authors
Nyombayire, Julien; Anzala, Omu; Gazzard, Brian; Karita, Etienne; Bergin, Philip; Hayes, Peter; Kopycinski, Jakub; Omosa-Manyonyi, Gloria; Jackson, Akil; Bizimana, Jean; Farah, Bashir; Sayeed, Eddy; Parks, Christopher L.; Makoto Inoue; Takashi Hironaka; Hiroto Hara; Tsugumine Shu; Tetsuro Matano; Dally, Len; Barin, Burc
- Abstract
<bold>Background: </bold> We report the first-in-human safety and immunogenicity assessment of a prototype intranasally administered, replication-competent Sendai virus (SeV)-vectored, human immunodeficiency virus type 1 (HIV-1) vaccine.<bold>Methods: </bold> Sixty-five HIV-1-uninfected adults in Kenya, Rwanda, and the United Kingdom were assigned to receive 1 of 4 prime-boost regimens (administered at 0 and 4 months, respectively; ratio of vaccine to placebo recipients, 12:4): priming with a lower-dose SeV-Gag given intranasally, followed by boosting with an adenovirus 35-vectored vaccine encoding HIV-1 Gag, reverse transcriptase, integrase, and Nef (Ad35-GRIN) given intramuscularly (SLA); priming with a higher-dose SeV-Gag given intranasally, followed by boosting with Ad35-GRIN given intramuscularly (SHA); priming with Ad35-GRIN given intramuscularly, followed by boosting with a higher-dose SeV-Gag given intranasally (ASH); and priming and boosting with a higher-dose SeV-Gag given intranasally (SHSH).<bold>Results: </bold> All vaccine regimens were well tolerated. Gag-specific IFN-γ enzyme-linked immunospot-determined response rates and geometric mean responses were higher (96% and 248 spot-forming units, respectively) in groups primed with SeV-Gag and boosted with Ad35-GRIN (SLA and SHA) than those after a single dose of Ad35-GRIN (56% and 54 spot-forming units, respectively) or SeV-Gag (55% and 59 spot-forming units, respectively); responses persisted for ≥8 months after completion of the prime-boost regimen. Functional CD8+ T-cell responses with greater breadth, magnitude, and frequency in a viral inhibition assay were also seen in the SLA and SHA groups after Ad35-GRIN boost, compared with those who received either vaccine alone. SeV-Gag did not boost T-cell counts in the ASH group. In contrast, the highest Gag-specific antibody titers were seen in the ASH group. Mucosal antibody responses were sporadic.<bold>Conclusions: </bold> SeV-Gag primed functional, durable HIV-specific T-cell responses and boosted antibody responses. The prime-boost sequence appears to determine which arm of the immune response is stimulated.<bold>Clinical Trials Registration: </bold> NCT01705990.
- Subjects
KENYA; RWANDA; SENDAI virus diseases; RNA virus infections; T-cell lymphoma; ANTIBODY formation; REVERSE transcriptase; HIV prevention; INTRANASAL medication; AIDS vaccines; CELLULAR immunity; CLINICAL trials; COMPARATIVE studies; GENES; HIV; HIV infections; IMMUNIZATION; RESEARCH methodology; MEDICAL cooperation; PARAMYXOVIRUSES; RESEARCH; T cells; VACCINES; VIRAL antibodies; EVALUATION research; RANDOMIZED controlled trials; PHYSIOLOGY
- Publication
Journal of Infectious Diseases, 2017, Vol 215, Issue 1, p95
- ISSN
0022-1899
- Publication type
journal article
- DOI
10.1093/infdis/jiw500